The central hypothesis of this proposal is that human CLL associated or specific antigens exist. However, due to defects in T cell recognition and effector function in the tumor bearing host and/or inefficient or ineffective antigen presentation by the tumor cells, no clinically significant anti-tumor T cell response to CLL is generated. The objective of this proposal is to attempt to develop more effective, novel adoptive T cell immunotherapy to eradicate minimal residual leukemia cells in patients with CLL. We propose undertake basic laboratory experiments, pre-clinical studies and scale up, and clinical trials necessary to achieve this objective. For this, we have the following specific aims: (1) determine the mechanism whereby T cells in patients with CLL are induced to become immune- incompetent; (2) examine the signaling events that follow CD40-ligation necessary and sufficient to induce competent antigen presentation by CLL cells; (3) develop and optimize methodologies to generate and expand autologous T cells and to undertake clinical trials of adoptive immunotherapy; (4) develop and optimize methodologies to generate and expand allogeneic T cells for adoptive immunotherapy following allogeneic stem cell transplantation (SCT); (5) determine the impact of autologous or allogeneic adoptive T cell immunotherapy in patients with minimal disease assessing PCR as a surrogate endpoint, relapse, and survival. The findings on signaling in CLL cells will likely have relevance to studies proposed in Project 1 and Project 2. This project is highly interactive and dependent upon investigators and studies proposed in Project 3.